The objective of this work is to determine how the activity of glycogen synthase is regulated. The proposed studies center around the role of glycogen synthase kinases in the inactivation (by phosphorylation) of glycogen synthase. We have recently discovered that most of the glycogen synthase kinase activity in most mammalian tissues is cyclic AMP-independent in contrast to that which has previously been recognized (cyclic AMP-dependent protein kinase). Because these kinases differ in many important respects, the proposed studies will compare their effects on glycogen synthase and attempt to determine the physiological roles of each of these enzymes. Specifically we propose the following: 1) To purify and characterize the cyclic AMP-independent kinases and compare their properties to those of purified cyclic AMP-dependent protein kinase catalytic subunit. 2) To study the properties of glycogen synthase inactivated by each of these enzymes. 3) To determine the factors which regulate the activity of these kinases by utilizing intact cells as well as purified enzyme preparations. Because the mechanisms by which glycogen synthase kinase is regulated are only partly understood (particularly with reference to the action of insulin and alpha adrenergic agents) these studies should enhance our understanding of these mechanisms. BIBLIOGRAPHIC REFERENCE: Reimann, E.M. and K.K. Schlender. Multiple forms of glycogen synthase kinase: isolation of forms which are independent of cyclic AMP. J. Cyclic Nucleotide Res. 2 (1976) 39-46.